Atezolizumab and Sipuleucel-T in Treating Patients with Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer
This randomized phase Ib trial study will assess the sequence of the administration of atezolizumab and sipuleucel-T and to see how well they work in treating patients with castration resistant metastatic prostate cancer without symptoms or with minimal symptoms. Atezolizumab may enhance the body's ability to recognize abnormal, tumor cells. Vaccines, such as sipuleucel-T, made from a person’s white blood cells mixed with tumor proteins may help the body build an effective immune response to kill prostate tumor cells. Giving atezolizumab and sipuleucel-T may work better in treating patients with castration resistant metastatic prostate cancer.
- Progressive castration-resistant metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
- Patients must have measurable or non-measurable disease * Measurable disease ** For visceral or extra-nodal lesions to be considered measurable, they must be >= 10 mm in one dimension, using spiral computed tomography (CT) ** For lymph nodes to be considered measureable (i.e., target or evaluable lesions), they must be >= 20 mm in at least one dimension, using spiral CT * Non-measurable disease ** All other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions. *** Lesions that are considered non-measurable include bone lesions (only)
- Asymptomatic or mildly symptomatic from prostate cancer
- Patients must have progressive disease at study entry defined as one or more of the following three criteria that occurred while the patient was on androgen deprivation therapy; for patients enrolling on the basis of soft tissue or bone progression, the baseline scan must show progression relative to a comparison scan; if the comparison scan is not available, the baseline scan report must reference the previous scan to document progression
- PSA progression defined by a minimum of two rising PSA levels with an interval of >= 1 week between each determination; patients who received an anti-androgen must have progression documented by a minimum of two rising PSA levels with an interval of >= 1 week between each determination such that at least the second of these rises is > 4 weeks since last flutamide or > 6 weeks since last bicalutamide or nilutamide; the PSA value at the screening should be > 2 ug/L (2 ng/mL)
- Soft tissue disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study); in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm; (Note: the appearance of one or more new non-osseous lesions is also considered progression); clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, palpable lymph nodes) and at least 10 mm in diameter as assessed using calipers (e.g., skin nodules) * Per Prostate Cancer Working Group 2 (PCWG2): Visceral (lung, liver adrenal) or extranodal lesions need to be >= 10 mm in one dimension, using spiral CT; however, lymph nodes need to be >= 20 mm in at least one dimension to be considered new
- Bone disease progression is defined by PCWG2 as two or more new lesions on bone scan
- No treatment with prior sipuleucel-T, PD-1 inhibitor, MPDL3280A or any other PD-L1 inhibitor, taxane-based chemotherapy for metastatic disease
- Patients who received prior taxane-based chemotherapy as neoadjuvant or adjuvant therapy for local disease, or who received taxane-based therapy in the PSA clinical (non-metastatic) state is allowable provided that the total duration of exposure was six cycles or less and chemotherapy was completed more than 6 months prior to registration
- Taxane-based chemotherapy that was aborted due to allergic reactions or intolerance to chemotherapy and therefore received 1 cycle of prior therapy is allowable
- No treatment with any of the following for prostate cancer within 4 weeks prior to enrollment:
- Hormonal therapy (e.g., androgen receptor [AR] antagonists, 5 alpha reductase inhibitors, estrogens)
- Note: Treatment with bicalutamide and nilutamide within 6 weeks prior to enrollment is not allowed; treatment with flutamide within 4 weeks prior to enrollment is not allowed; treatment with all other gonadotrophin-releasing hormone (GnRH) analogues or antagonists is allowed * Chemotherapy * Biologic therapy * Investigational therapy * Immunotherapy
- No use of herbal products that may decrease PSA levels within 4 weeks prior to enrollment
- No use of systemic steroids greater than the equivalent of 10 mg of prednisone/prednisolone per day within 4 weeks prior to enrollment
- No prior use of ketoconazole for greater than 7 days
- No prior radiation therapy or radionuclide therapy for the treatment of metastasis within four weeks prior to enrollment
- Patients must maintain ongoing androgen deprivation therapy with a GnRH analogue, antagonist, or bilateral orchiectomy (i.e., surgical or medical castration)
- No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)
- No planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
- No structurally unstable bone lesions suggesting impending fracture
- No clinically significant cardiovascular disease including: * Myocardial infarction (MI) within 6 months * Uncontrolled angina within 3 months * Chronic heart failure (CHF) with New York Heart Association (NYHA) class 3 or 4, or patients with NYHA class 3 or 4 in the past, unless a screening echo or multigated acquisition scan (MUGA) performed within three months demonstrates an ejection fraction (EF) > 45% * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsades de pointes) * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place * Hypotension (systolic blood pressure [BP] < 86 mmHg) or bradycardia (< 50 beat per minute [bpm]) at screening * Uncontrolled hypertension (systolic BP >170 mmHg or diastolic BP >105 mmHg at screening)
- No gastrointestinal (GI) disorder that negatively affects absorption
- No major surgery within 4 weeks prior to enrollment
- Signed informed consent form (ICF)
- A score of 0-1 on Brief Pain Inventory (BPI)-Short Form (SF) question 3 (worst pain in last 24 hours) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic
- Ability and willingness to comply with the requirements of the study protocol
- Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks are preferred) or at least 5 unstained slides, with an associated pathology report, for central testing of tumor PD-L1 expression * Tumor tissue should be of good quality based on total and viable tumor content; fine needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable; for core-needle biopsy specimens, at least three cores should be submitted for evaluation * Patients who do not have tissue specimens meeting eligibility requirements may undergo a biopsy during the screening period; acceptable samples include core needle biopsies for deep tumor tissue (minimum of three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions * Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable
- Absolute neutrophil count (ANC) >= 1500 cells/uL
- White blood cell (WBC) counts > 2500/uL
- Lymphocyte count >= 300/uL
- Platelet count >= 100,000/uL; for patients with hematologic malignancies, platelet count >= 75,000/uL
- Hemoglobin >= 9.0 g/dL
- Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception: * Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN with the following exception: * Patients with liver involvement: AST and/or ALT =< 5 x ULN
- Alkaline phosphatase =< 2.5 x ULN with the following exception: * Patients with documented liver involvement or bone metastases: alkaline phosphatase =< 5 x ULN
- Serum creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation
- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 for patients with solid malignancies
- For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 6 months after the last dose of MPDL3280A
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN * This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose
- Any approved anticancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 3 weeks prior to initiation of study treatment; however, the following are allowed: * Hormone-replacement therapy or oral contraceptives * Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1) * Palliative radiotherapy for bone metastases > 2 weeks prior to cycle 1, day 1
- Adverse events (AEs) from prior anticancer therapy that have not resolved to grade =< 1 except for alopecia
- Bisphosphonate therapy for symptomatic hypercalcemia * Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
- Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
- Patients with acute leukemias, accelerated/blast phase chronic myelogenous leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma
- Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases * Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met: ** Evaluable or measurable disease outside the CNS ** No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm) ** No history of intracranial hemorrhage or spinal cord hemorrhage ** No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted No neurosurgical resection or brain biopsy within 28 days prior to cycle 1, day 1 * Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following: ** Radiographic demonstration of improvement upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study ** No stereotactic radiation or whole-brain radiation within 28 days prior to cycle 1, day 1 ** Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
- Pregnancy, lactation, or breastfeeding
- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
- Inability to comply with study and follow-up procedures
- History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Bell’s palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis * Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible * Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible * Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: ** Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations ** Rash must cover less than 10% of body surface area (BSA) ** Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) ** No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
- History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic or acute) or hepatitis C infection * Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
- Active tuberculosis
- Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1
- Received oral or IV antibiotics within 2 weeks prior to cycle 1, day 1 * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
- Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure during the course of the study
- Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study * Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to cycle 1, day 1 or at any time during the study
- Malignancies other than the disease under study within 5 years prior to cycle 1, day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score =< 6, and prostate-specific antigen [PSA] =< 10 mg/mL, etc)
- MEDICATION-RELATED EXCLUSION CRITERIA:
- Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents * Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met: ** Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last dose ** No history of severe immune-related adverse effects from anti-CTLA 4 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4)
- Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to cycle 1, day 1
- Treatment with investigational agent within 4 weeks prior to cycle 1, day 1 (or within five half lives of the investigational product, whichever is longer)
- Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1 * Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
Locations & Contacts
Contact: Charles Joel Rosser
Trial Objectives and Outline
I. To characterize the molecular changes (i.e., reduction in quantity of cell free deoxyribonucleic acid (DNA) associated with tumor and induction of favorable genomic profile associated with ribonucleic acid (RNA) from circulating tumor cells and peripheral blood mononuclear cells (PBMC) between the two study arms.
II. To characterize the immunogenicity profile of peripheral blood mononuclear cell (i.e., induction of total nucleated cell [TNC], CD3+, CD4+, CD8+, CD56, CD 68 [antigen presenting cells] cells) between the two study arms.
III. To characterize the enzyme-linked immunosorbent spot assay (ELISPOT) for prostatic acid phosphatase (PAP) and PA2014.
IV. To characterize the cytokine profile between the two study arms at various time points (i.e., baseline, immediately after completing drug 1, immediately after completing drug 2, then at 3, 6 and 12 months) in treated patients.
V. To compare the safety and tolerability of sequential atezolizumab (MPDL3280A) followed by sipuleucel-T (Arm 1) versus (vs.) sipuleucel-T followed by MPDL3280A (Arm 2) in patients who have asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (CRPC), not previously treated with docetaxel, cabazitaxel, abiraterone or enzalutamide.
I. To assess anti-tumor activity in Arm 1 and Arm 2 as determined by objective response rate.
2. To assess progression-free survival, duration of response and effect on performance status in Arm 1 and Arm 2 of all treated patients.
3. To assess PD-1, PD-2, PD-L1 tissue expression by immunohistochemical staining of archived prostate biopsy, prostatectomy and/or biopsy of metastatic lesion of CRPC.
4. To monitor technetium TC-99m (Tc-99) bone scan imaging on therapy to characterize treatment response and link molecular characteristics above, i.e., quantity of cell free DNA, transcriptomic of circulating tumor cell (CTC), PBMC levels/ratio, cytokines and tissue expression levels of PD-1, PD-2 and PD-L1 to bone scan imaging and outcomes.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on weeks 1 and 4 and sipuleucel-T IV over 60 minutes on weeks 6, 8, and 10. Beginning week 13, patients that do not experience any dose limiting toxicity continue to receive atezolizumab IV over 30-60 minutes every 3 weeks in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive sipuleucel-T IV over 60 minutes on weeks 1, 3, and 5 and atezolizumab IV over 30-60 minutes on weeks 7 and 10. Beginning week 13, patients that do not experience any dose limiting toxicity continue to receive atezolizumab IV over 30-60 minutes every 3 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 5 years.
Trial Phase & Type
University of Hawaii Cancer Center
Charles Joel Rosser
Secondary IDs NCI-2017-00247
Clinicaltrials.gov ID NCT03024216